Thrombin is an important agonist for platelet activation and plays a major role in hemostasis and thrombosis. Thrombin activates platelets mainly through protease-activated receptor 1 (PAR1 ), PAR4, and glycoprotein lb. Because adenosine diphosphate and thromboxane A2 have been shown to cause platelet aggregation by concomitant signaling through Gq and Gi pathways, we investigated whether coactivation of Gq and Gi signaling pathways is the general mechanism by which PAR1 and PAR4 agonists also activate platelet fibrinogen receptor (αIIbβ3). A PAR1-activating peptide, SFLLRN, and PAR4-activating peptides GYPGKF and AYPGKF, caused inhibition of stimulated adenylyl cyclase in human platelets but not in the presence of either Ro 31-8220, a protein kinase C selective inhibitor that abolishes secretion, or AR-C66096, a P2Y12 receptor-selective antagonist; α-thrombin-induced inhibition of adenylyl cyclase was also blocked by Ro 31-8220 or AR-C66096. In platelets from a P2Y12 receptor-defective patient, α-thrombin, SFLLRN, and GYPGKF also failed to inhibit adenylyl cyclase. In platelets from mice lacking the P2Y12 receptor, neither α-thrombin nor AYPGKF caused inhibition of adenylyl cyclase. Furthermore, AR-C66096 caused a rightward shift of human platelet aggregation induced by the lower concentrations of α-thrombin and AYPGKF but had no effect at higher concentrations. Similar results were obtained with platelets from mice deficient in the P2Y12. We conclude that (1) thrombin- and thrombin receptor-activating peptide-induced inhibition of adenylyl cyclase in platelets depends exclusively on secreted adenosine diphosphate that stimulates Gi signaling pathways and (2) thrombin and thrombin receptor-activating peptides cause platelet aggregation independently of Gi signaling.
Protease-activated receptors 1 and 4 do not stimulate G(i) signaling pathways in the absence of secreted ADP and cause human platelet aggregation independently of G(i) signaling / S. Kim, C. Foster, A. Lecchi, T. Quinton, D. Prosser, J. Jin, M. Cattaneo, S. Kunapuli. - In: BLOOD. - ISSN 0006-4971. - 99:10(2002), pp. 3629-3636.
|Titolo:||Protease-activated receptors 1 and 4 do not stimulate G(i) signaling pathways in the absence of secreted ADP and cause human platelet aggregation independently of G(i) signaling|
CATTANEO, MARCO NATALE (Penultimo)
|Settore Scientifico Disciplinare:||Settore MED/09 - Medicina Interna|
|Data di pubblicazione:||2002|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1182/blood.V99.10.3629|
|Appare nelle tipologie:||01 - Articolo su periodico|